Medicine & Health

Publication Search Results

Now showing 1 - 10 of 43
  • (2020) Chen, Kerrie-Anne
    Thesis
    This thesis examines the clinical translation of two novel therapeutic drugs in rare paediatric neurological disease via expanded access programs (EAP). Patients with rare diseases commonly encounter barriers to care and lack of disease-modifying treatments. EAPs help address this need by providing access to therapeutic drugs before commercial availability, however, there is usually limited knowledge regarding the safety and full impact of the drug. Two drugs were recently made available via an EAP for children in New South Wales: cannabidiol for paediatric drug-resistant epilepsy (DRE) and nusinersen for spinal muscular atrophy (SMA). In a time when there was no evidence regarding the use of cannabidiol in paediatric DRE, an EAP was established due to unprecedented patient demand. Our study analysed the safety, adverse effects and preliminary efficacy of cannabidiol in patients with DRE. Cannabidiol was well tolerated, with sedation commonly reported (37.5%). Elevated transaminases were seen in 5% and demonstrated the necessity of medical monitoring. Although many patients reported improved overall health, indirect measures of seizure control did not show improvement, thus signifying the need for larger, randomised-controlled trials. In children with SMA type 1 (SMA1) treated with nusinersen, respiratory, bulbar and nutritional outcomes were analysed, as previous studies had demonstrated increased survival and motor function but had not assessed the broader impact on the burden of disease. Our study demonstrated substantial ongoing comorbidities due to respiratory and bulbar weakness, with the need for ongoing nocturnal noninvasive ventilation, gastrostomy feeding and recurrent acute hospitalisations. Greater burden of disease was seen more in patients with two SMN2 copies. Most children showed improvement in motor outcome assessments, a stark change in the natural history of SMA. These findings show the impact of nusinersen in modifying the phenotype of children with SMA1, yet ongoing significant morbidities and requirement for multidisciplinary supportive medical care. In conclusion, these studies provide additional real-world clinical data on the implementation and extent of efficacy of two novel drugs for rare neurological diseases. EAPs serves to address an unmet clinical need and facilitate the translation of research into practice to advance future health practice and research in rare diseases.

  • (2021) Cheng, Lap
    Thesis
    Chronic kidney disease (CKD) is a major public health issue affecting 10% of the global population and resulting in 1.2 million deaths. The risk of all-cause and cardiovascular mortality is inversely proportional to declining eGFR such that individuals with CKD are more likely to die, primarily due to a cardiovascular cause, than survive to the point of requiring dialysis. These poor outcomes are related to a myriad of factors including multimorbidity, medial vascular calcification and underlying haemostatic dysfunction. Polypharmacy is a key consequence of the disease burden experienced by CKD patients. It is linked with poor adherence, adverse drug reactions, falls and increased hospitalisations. A post-hoc analysis of the CKD-FIX study was conducted to assess the prevalence and predictors of polypharmacy in CKD patients. It found that polypharmacy, defined as ≥5 medications, and hyperpolypharmacy, defined as ≥10 medications, were found in 77.5% and 34.3% of patients respectively. Age ≥65 yrs, diabetes, cardiovascular disease and hyperlipidemia were independently associated with polypharmacy. However, limiting polypharmacy via appropriate prescribing is hampered by the lack of data in patients with advanced CKD. Despite the disproportionate cardiovascular disease burden in CKD, the benefits and risks of dual antiplatelet therapy are not known. Therefore a systematic review of randomised controlled trials on the effectiveness of dual antiplatelet therapy in CKD was conducted. Nineteen trials with 27,308 participants were analysed with all but 3 trials excluding participants with dialysis-dependent kidney failure. Compared with aspirin monotherapy or no study medication, P2Y12 inhibitor-based dual antiplatelet therapy significantly reduced the risks of major adverse cardiovascular events, myocardial infarction and stroke; but increased the risk of major bleeding. There was insufficient evidence to conclude whether patients with advanced stages of CKD and dialysis-dependent kidney failure derived benefit. In conclusion, CKD patients represent an expanding population that is at high risk of adverse outcomes. Polypharmacy is common in patients with CKD and is related to age and multimorbidity. Further research on medication appropriateness and deprescribing are needed. In particular, adequately powered randomized trials are required to evaluate the effectiveness of dual antiplatelet therapy in patients with advanced stages of CKD and cardiovascular disease.

  • (2022) Ma, Trevor
    Thesis
    The aim of this study was to estimate the prevalence and identify potential determinants of cardiometabolic disease (CMD) in people with psychotic disorders in secure settings and compare these to people with psychotic disorders in the community. A systematic review of the literature was undertaken to determine existing rates of CMD indicators in people with psychotic disorders in secure settings. Data from a comprehensive health and wellbeing survey, the Forensic Mental Health Patient Survey (FMHPS), were obtained to determine the prevalence and determinants of CMD indicators in a sample of forensic patients. Findings were directly compared to a sample of people with psychotic disorders living in the community using data from the second Australian National Survey of High Impact Psychosis (SHIP). The weighted pooled prevalence rates from the reviewed studies were hypertension 25.0% (N=857, 95% CI 22.1-27.9), dyslipidaemia 29.2% (N=1,135, 95% CI 26.6-31.9), diabetes 11.2% (N=2,582, 95% CI 9.9-12.4), being overweight or obese 72.4% (N=840, 95% CI 69.4-75.5), cardiovascular disease 15.6% (N=1,047, 95% CI 13.4-17.8) and metabolic syndrome 23.5% (N=1,390, 95% CI 21.3-25.7). The prevalence of CMD indicators in the reviewed studies were predominantly higher compared to the general population. When directly compared, the forensic patient sample were older, more likely to be male, and more likely to be of Aboriginal and/or Torres Strait Islander background, than the community-based psychosis sample. The former also had higher rates of polypharmacy, clozapine prescribing, physical activity, and food consumption. However, on multivariate analysis, the forensic patients had a lower prevalence of hypertension (OR 0.36, 95% CI 0.23-0.57) and metabolic syndrome (OR 0.41, 95% CI 0.25-0.67) compared to the community-based psychosis sample. There are clearly important differences in the sociodemographic characteristics, treatment needs and lifestyle practices of forensic patients in secure settings and there may be aspects of secure care that actually reduce CMD risk, however the resultant impact on CMD prevalence is complex. Forensic patients in secure settings require early detection and assertive treatment of CMD indicators and further research to assess the feasibility and effectiveness of these interventions in secure settings is required.

  • (2021) Byrne, Bonita
    Thesis
    Background: Aboriginal and Torres Strait Islander people are more likely to abstain from alcohol than non-Indigenous Australians, however, they are more likely to experience harms related to their own or others’ alcohol use. Factors such as lower socioeconomic status and poorer access to appropriate services have been identified as potential risk factors for increased alcohol-related harms. Another potential factor that has not yet been explored in the published literature is lateral violence as a result of conflict in Aboriginal communities, and how that conflict contributes to alcohol-related harms. Aims: This research investigates the reasons why conflict exists in Aboriginal communities. It explores how conflict is associated with alcohol-related harms experienced by Aboriginal Australians. Methods: A narrative literature review using systematic search strategies was conducted to identify published literature on the association between conflict and substance misuse in Aboriginal communities in Australia. This review searched 14 databases. Abstracts were systematically screened against inclusion criteria. Next, qualitative interviews were conducted with nine Aboriginal Elders and community members to explore their lived experiences with conflict and alcohol-related harms in their communities and potential healing approaches to address this. Interviews were conducted using a yarning method in one-on-one interviews to elicit participants’ stories. A thematic analysis was conducted using inductive and deductive coding. Results: The literature review identified nine studies which considered conflict and its association with substance misuse in Aboriginal communities in Australia. The main factors that contribute to alcohol use, conflict and the association between the two were colonisation, lower socioeconomic status, remoteness and social identity. Key themes from participants’ lived experience with conflict and alcohol-related harms identified in the interviews were: breakdown of family and community due to colonisation and displacement, alcohol use in the community, and experience of racism. Key recommended strategies for healing included cultural programs and increasing respect for Elders. Conclusion: This study furthered our understanding of the effects of colonisation on Aboriginal communities today. It identified how the breakdown of family and kinship ties have contributed to conflict and alcohol-related harms experienced by Aboriginal communities. It points to potential ways to build resilience among Aboriginal communities and prevent alcohol misuse and conflict.

  • (2020) Masand, Natasha
    Thesis
    DNA cytosine methylation is an important epigenetic modification that plays a key role in gene expression. DNA methylation has been shown to be involved in numerous processes, including X-chromosome inactivation in mammals, retrotransposon silencing, genomic imprinting, carcinogenesis and the regulation of tissue specific gene expression during development. Gene expression is tightly regulated via DNA methylation (5mC) and the aberrant expression of meiotic genes in mitotic cells via CpG promoter hypomethylation has been proposed to cause cancer. Cancer/Testis Antigens (CTAs) are a group of genes that encode tumour specific antigens and are expressed in the testis, certain cancers but not in normal post-natal somatic tissues. CpG island methylation and histone modifications appear to play a role in the epigenetic regulation of CTA expression, however, very little is known about their functions in vivo. A widely studied but poorly understood question to date is the mechanisms behind aberrant CTA reactivation in cancer. Given that 5mC mediated gene repression has been found to exist in vertebrate genomes and CTAs have also been identified to be a subset of highly evolutionarily conserved genes, it is critical to understand the role of 5mC mediated CTA silencing in vertebrates. By gaining a deeper understanding into the mechanisms behind this highly conserved pattern of gene repression on a specific subset of genes, we would be able to identify methods to prevent aberrant gene expression. In this study, I analysed publicly available whole genome bisulfite sequencing (WGBS), RNA-seq and chromatin immuno-precipitation followed by massively parallel sequencing (ChIP-seq) data of developing embryonic and adult somatic tissue of 3 vertebrate species to elucidate the evolutionary epigenetic regulation of CTAs in vertebrate genomes. Integrative WGBS, RNA-seq and ChIP-seq analysis revealed that CTAs are evolutionarily conserved in zebrafish, mice and humans and mechanisms of their epigenetic regulation are also conserved. I observed that histone modifications could potentially serve as an indicator of the methylation status of CTA gene promoters and that the expression of CTAs was inversely related to gene promoter 5mC levels. I demonstrate that CTAs when over-expressed cause embryonic lethality in zebrafish and the same genes are aberrantly hypomethylated at their CpG islands in a subset of human cancers. Overall, my work shows that CTAs are epigenetically regulated in an evolutionarily conserved manner and possibly via a conserved transcription factor, ETS1, that is expressed both in embryonic and cancerous tissue.

  • (2022) Patterson, Kate
    Thesis
    3D computer generated biomedical animations can help audiences understand and contextualise scientific information that can be challenging to communicate due to resolution and complexity. Biomedical animators bring together multiple sources of authentic scientific data, to translate abstract information into a visual form through storytelling and visualisation. The field of biomedical animation has emerged from a long history of science visualisation and science-art endeavours, and despite there being rich discourse in the fields of data visualisation and science communication, the academic literature in the field of biomedical animation is limited, and focussed on the technical methods for visualisation, or the role these animations play in scientific research, rather than the processes through which they are created. However, as the field matures, there is a need for a deeper understanding of the creative process, and the field is now poised to expose and characterise these aspects, particularly from the perspective of the practitioner. This practice-based research project aims to expose and characterise both the visible and invisible factors that influence my personal process of creating a biomedical animation, and the tacit dimensions that influence orchestrated design choices. This research project employs a multi-method and reflective practice approach with disciplined capture and documentation of critical moments of self-reflection, that ultimately comprise the data for analysis. Thematic analysis was then used to analyse the data, and to identify themes that could contribute to frameworks that represent my personal process(es) in creating 3D biomedical animations. This has allowed me to identify and contextualise my creative process both in terms of my personal and professional position as well as within the field more broadly. I am now able to better advocate for the intangible and often undervalued aspects of my creative practice, and can articulate how a hierarchical decision matrix that considers multiple inputs contributes to my creative process. These insights will also be relevant to others in the field of biomedical animation and in the field of design more broadly, who may gain a deeper insight into their own processes of working and ways of exploring creative practice.

  • (2022) Phan, Kevin
    Thesis
    Background: Anterior lumbar interbody fusion (ALIF) remains one of the mainstay surgical approaches in treating painful degenerative disc disease with or without segmental instability in the lower spine. The risk factors and complication profile for ALIF differs significantly from other established fusion techniques. Objectives: The goal of the first part of this thesis is to establish the factors associated with long-term clinical outcome (Chapter 2) and short-term perioperative outcomes (Chapter 3) following ALIF. Chapter 4 focuses on the long-term radiographic evidence for biomaterial alternatives for ALIF implants, namely titanium (Ti)-coated PEEK integrated cages. Methods and Results: From a prospective cohort analysis of 147 patients undergoing ALIF, elderly age (≥64 years old) was associated with an increased rate of subsidence but does not affect clinical outcomes. Obesity was not associated with postoperative complications or follow-up patient-reported outcomes. Failed fusion was significantly higher for smokers, and they were significantly more likely than non-smokers to experience postoperative complications such as pseudoarthrosis. To assess risk factors for perioperative complications and readmissions after ALIF, the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was analysed. ALIF was associated with prolonged length of stay and higher rate of return to operating theatre compared to posterior lumbar fusion. Obesity and alcohol intake increased the risk of 30-day readmissions. Discharge to non-home destination following ALIF was independently associated with wound complications and venous thromboembolism. Finally, a prospective follow-up study was performed to determine the long-term radiographic outcome following ALIF using Ti-coated PEEK cages with allograft and INFUSE. Effective fusion was achieved at up to 24-month follow-up for various indications including degenerative spine/disc disease, low grade lumbar isthmic spondylolisthesis, spondylotic radiculopathy and discogenic low back pain. Conclusions: Collectively, this thesis highlights the importance of personalising the care of an ALIF surgery patient, through identification and optimization of individual risk factors for short-term and long-term outcomes, as well as through choice of implant biomaterial and design.

  • (2020) Ip, Matthew
    Thesis
    The "ophthalmohelioses" represent a conglomeration of ocular surface and adnexa disease strongly influenced by increased ultraviolet light B exposure. Despite overlapping pathogenesis pathways, the severity of these differs across the different spectrums. Ocular surface squamous neoplasia (OSSN), pterygium and conjunctival melanocytic lesions represent the three most impacting subtypes of such "ophthalmohelioses" affecting the ocular surface. OSSN represents a broad class of squamous dysplastic lesions ranging from benign papillomas till invasive squamous cell carcinomas. Melanocytic tumours such as primary acquired melanosis have a great propensity to become malignant, especially if cells are atypical. Finally, pterygium is a benign growth commonly treated with surgical excision, but patients often face an endless remitting-relapsing cycle of pterygium recurrence and repeat surgery. If untreated, patients sight limitation secondary to visual axis invasion. The early detection of OSSN, pterygium and melanocytic lesions is non-existent and often disease requires to be excised and subsequently microscopically analysed before a formal conclusion is made. For pterygium, the identification of Fuchs' Flecks at the head of pterygium may serve as satellite cells ahead of the main pterygium body. Handedness may serve a role in the eye in which pterygium is worse or develops. From a therapeutic point of view, these three "ophthalmohelioses" tend to recur consistently despite optimized treatments. This therapeutic dilemma presents themes of concern, including vision disruption, secondary to repeat surgeries given the relapsing-remitting characteristic of all three disease entities. Topical eye drops such as interferon alfa-2b combined with retinoic acid serve as a potential solution which offer superior tumour-free follow-up and rapid tumour resolution of OSSN or primary acquired melanosis lesions. The viral influence of human papilloma virus upon OSSN may be mitigated with the application of topical cidofovir. Additionally, specialized pterygium surgery may be an effective alternative to otherwise other subtypes of pterygium excision, others often being anatomically more destructive. At essence, a focus of novel therapeutic options that target pathways within "ophthalmoheliosis" pathogenesis is being presented within this thesis which may hopefully improve and expand ophthalmologist's arsenal against disease spectrums very relevant to the Australian populace.

  • (2020) Bakshi, Madhura
    Thesis
    Whole genome sequencing (WGS) is a powerful tool for diagnosis of Mendelian disorders. This study is aimed at evaluating the utility of WGS for molecular diagnosis of a multiethnic Intellectual Disability(ID) cohort. Individuals were recruited through the Clinical Genetics department of a tertiary hospital in New South Wales, Australia, over three years. All patients had varying degrees of syndromic or non-syndromic ID; some had neurological syndromes. WGS was undertaken using singleton, duo or trio approach after assessment of clinical features, family history and screening genetic investigations. Next Generation Sequencing (NGS) technology was utilised for sequencing and analysing genomic data at Genome.One, a NATA accredited WGS laboratory in Australia. Analysis included sequence variation and copy number limited to exonic and flanking splice site regions of known Mendelian disease-causing genes. Families where no diagnosis was made on initial analysis, were reanalysed two years later. A total of 46 probands from 43 families underwent WGS. There were 8/43 (18%) consanguineous families. A final diagnosis was made in 22/43 (51%) families. A variant providing a partial explanation of the phenotype was found in 3/43(6.9%) families. Actionable incidental findings were reported in 3/43 families. No copy number variants were identified. The RAS-MAPK pathway and microtubule related proteins emerged as predominant causative pathways within this phenotypically diverse cohort. Reanalysis revealed candidate variants in 6/14 families reanalysed representing a potential increased yield of 14%. In summary, application of WGS for investigation of an unselected ID cohort demonstrated a significant diagnostic yield. A clinical and genomic data review two years after the initial analysis was an achievable and worthwhile exercise, increasing the diagnostic yield to 65%.

  • (2021) Shamsa, Aiat
    Thesis
    Oocyte-secreted growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are critical paracrine regulators of female fertility. Recent studies demonstrated that serum concentrations are associated with the number of oocytes retrieved during IVF, and therefore potential clinical use as biomarkers. However, it is unknown if serum GDF9 or BMP15 is affected by the presence of endometriosis. An exploratory case-control study was prospectively performed on 60 women who underwent planned laparoscopy between April 2017 and August 2018 at two hospitals. GDF9 and BMP15 were measured by validated immunoassays in pre-operative serum samples. Data were analysed relative to laparoscopic assessment of endometriosis and staging. There were 35 women with confirmed laparoscopic diagnosis of endometriosis and 25 controls with no evidence of endometriosis at laparoscopy. GDF9 was detectable in 40% of controls and 48% of cases. There was no difference in median GDF9 concentrations between controls (20.0 pg/ml, range 20.0-2504 pg/ml) and cases (20.0 pg/ml, range 20.0-2963 pg/ml). BMP15 was detectable in 48% of controls and 58% of cases, with no difference in median concentrations between controls (26.5 pg/ml, range 24.0-1499 pg/ml) and cases (24.0 pg/ml, range 24.0-796 pg/ml). Furthermore, there were no significant differences in the proportion of detectable samples or concentrations of GDF9 or BMP15 with differing severities of endometriosis. In conclusion, serum concentrations of oocyte-secreted factors, GDF9 and BMP15 did not differ between control patients and patients with endometriosis. For clinical application of GDF9 and BMP15 serum biomarkers in reproductive medicine, quantitation in serum is unlikely to be aberrant due to the presence of endometriosis.